SIRT1 limits adipocyte hyperplasia through c-Myc inhibition
Open accessAbstract
The expansion of fat mass in the obese state is due to increased adipocyte hypertrophy and hyperplasia. The molecular mechanism that drives adipocyte hyperplasia remains unknown. The NAD(+)-dependent protein deacetylase sirtuin 1 (SIRT1), a key regulator of mammalian metabolism, maintains proper metabolic functions in many tissues, counteracting obesity. Here we report that differentiated adipocytes are hyperplastic when SIRT1 is knocked down stably in mouse 3T3-L1 preadipocytes. This phenotype is associated with dysregulated adipocyte metabolism and enhanced inflammation. We also demonstrate that SIRT1 is a key regulator of proliferation in preadipocytes. Quantitative proteomics reveal that the c-Myc pathway is altered to drive enhanced proliferation in SIRT1-silenced 3T3-L1 cells. Moreover, c-Myc is hyperacetylated, levels of p27 are reduced, and cyclin-dependent kinase 2 (CDK2) is activated upon SIRT1 reduction. Remarkably, differentiating SIRT1-silenced preadipocytes exhibit enhanced mitotic clonal expansion accompanied by reduced levels of p27 as well as elevated levels of CCAAT/enhancer-binding protein β (C/EBPβ) and c-Myc, which is also hyperacetylated. c-Myc activation and enhanced proliferation phenotype are also found to be SIRT1-dependent in proliferating mouse embryonic fibroblasts and differentiating human SW872 preadipocytes. Reducing both SIRT1 and c-Myc expression in 3T3-L1 cells simultaneously does not induce the adipocyte hyperplasia phenotype, confirming that SIRT1 controls adipocyte hyperplasia through c-Myc regulation. A better understanding of the molecular mechanisms of adipocyte hyperplasia will open new avenues toward understanding obesity.
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SIRT1 is needed for correct regulation of adipose tissue function.
“This indicates that SIRT1 is needed for a correct regulation of the adipose tissue function (Abdesselem et al., 2016).”
From Mitochondrial Activity and Dynamics Changes Regarding Metabolism in Ageing and Obesity (2017) · cites this paper as Abdesselem et al., 2016
A key role of SIRT1 in hyperplasia of adipocytes has been suggested.
“Very recently, a key role of SIRT1 in hyperplasia, the increase of cell number, of adipocytes, has been suggested.”
From Mitochondrial Activity and Dynamics Changes Regarding Metabolism in Ageing and Obesity (2017) · cites this paper as Abdesselem et al., 2016
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Mitochondrial Activity and Dynamics Changes Regarding Metabolism in Ageing and Obesity
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“This indicates that SIRT1 is needed for a correct regulation of the adipose tissue function (Abdesselem et al., 2016).”
BackgroundInfluential
- Authors
- Abdesselem, H., Madani, A., Hani, A., Al-Noubi, M., Goswami, N., Ben Hamidane, H., Billing, A. M., Pasquier, J., Bonkowski, M. S., Halabi, N., Dalloul, R., Sheriff, M. Z., Mesaeli, N., ElRayess, M., Sinclair, D. A., Graumann, J., & Mazloum, N. A.
- Affiliations
- Weill Cornell Medical College in Qatar (QA)
- Harvard University (US)
- Anti-Doping Laboratory (QA)
- Corresponding author
- Mazloum, Nayef A.
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2016-01
- Volume
- 291
- Issue
- 5
- Pages
- 2119-2135
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC4732199
- OpenAlex
- W2196929460
- Cited by
- 56
- References
- 43
- Citations by year
- 2026: 2 · 2025: 8 · 2024: 7 · 2023: 8 · 2022: 4 · 2021: 4 · 2020: 3 · 2019: 3 · 2018: 5 · 2017: 4 · 2016: 7 · 2015: 1
- FWCI
- 2.84
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- GlaxoSmithKline
- Qatar Foundation
- Weill Cornell Medicine - Qatar
- National Institute on Aging (R37AG028730)
- Topics
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- SIRT1, adipocyte hyperplasia, c-Myc, adipocyte proliferation, preadipocyte differentiation, obesity, protein deacetylation, p27, CDK2, C/EBPβ, adipocyte metabolism, adipose tissue inflammation, mitotic clonal expansion
- MeSH terms
- Animals, Cell Differentiation, Fibroblasts, Gene Expression Regulation, Humans, Hyperplasia, Hypertrophy, Inflammation, Obesity, Proto-Oncogene Proteins c-myc, Adipocytes, Gene Silencing, CCAAT-Enhancer-Binding Protein-beta, Proteomics, 3T3-L1 Cells, Cell Proliferation, Mice, Sirtuin 1, HEK293 Cells
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